Bacterial infection in the lung and its complications are major causes of morbidity and mortality, especially in patients suffering from cystic fibrosis. Current mode of treatments for these infections requires delivery of antibiotics to the lung tissue. These delivery techniques are either invasive and require hospitalization or trained medical personnel (e.g., intravenous or intramuscular injections), suffer from poor bioavailability (e.g., oral doses), and may have other drawbacks such as adverse effects associated with systemic drug exposure. Local administration of therapeutics via inhalation is a preferred mode of delivery, since it is non-invasive, convenient, does not require hospitalization, and reduces systemic exposure and its potential related adverse side-effects. However, delivery of therapeutic agents such as antibiotics via inhalation is generally ineffective due to low delivery efficiency and high clearance. A more effective method for drug delivery of antibiotics to the lung via inhalation is needed.
Meropenem, a β-lactam antibiotic, is currently one of the most potent antibiotics available for intravenous therapy against a range of pathogenic bacteria, such as Pseudomonas aeruginosa (MIC90 is about 8 μg/mL), the most frequent pathogen acquired by subjects with cystic fibrosis with lung airway infections. A conventional pharmaceutical composition of meropenem is not suitable for oral administration because of poor absorption. Although meropenem can be developed as an inhalable product, its high water solubility (>1 mg/mL) restricts the possible means of administration, such that a nebulized solution is the only option. The dose of therapeutic agent when administered in a nebulized solution is limited by its solubility, such that there is a specific maximum drug load per dose. Dosed as a solution (e.g., by nebulizer) the drug likely will clear quite rapidly from the lungs into systemic circulation, leaving limited local exposure in the lungs, and thus frequent dosing would be required. Furthermore, nebulization is a difficult and time-consuming procedure that, when used chronically (e.g., administered daily for over 30 days), significantly decreases patient life quality.
Meropenem may benefit from new methods and pharmaceutical compositions for inhalational administration, such as development into a dry-powder inhalable (DPI) drug product, which is a preferred mode of therapeutic delivery over nebulization. Delivery by DPI achieves greater drug load per dose than that of a nebulized solution. In addition, this delivery method circumvents the inconveniences to patients that are associated with nebulization. To achieve this, a particle-based formulation of meropenem must be developed by producing an improved water-insoluble form and formulation of meropenem. To effectively deliver the drug particles to the lung tissues, the particles must also overcome the mucus barrier. The mucus layer present at various points of entry into the body, including the eyes, nose, lungs, gastrointestinal tract, and female reproductive tract, serves to protect the body against pathogens, allergens, and debris by effectively trapping and quickly removing them via mucus turnover. For effective delivery of therapeutic particles via mucus membranes, the particles must be able to readily penetrate the mucus layer to avoid mucus adhesion and rapid mucus clearance. However, it is often difficult for particles administered via inhalation to be delivered to a tissue of the respiratory tract (e.g., lung, trachea, or bronchus) in effective amounts due to rapid clearance and/or other reasons. Thus, new pharmaceutical compositions and formulations to deliver therapeutic agents, such as meropenem, to the lung with a high drug concentration per dose and effective penetration through the mucus barrier are needed.